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Biomedical subjects

J R Snapper

Publications and source records attributed to J R Snapper.

At least 55 records · Page 3Linked to original sources
PubMed1985

Relation of blood-free to blood-inclusive postmortem lung water measurements in sheep.

Our purpose was to see if the postmortem weight ratio of extravascular lung water to blood-free dry lung (blood-free ratio) was related to similar ratios in blood-inclusive lung and in blood. We developed linear regressions of blood-free ratio on ratios for blood-inclusive lung and blood together and for blood-inclusive lung alone for 73 sheep studied under 11 different protocols and for two subgroups of sheep, one with plasma space expansion and the other without expansion. The relation of ratios of blood-free to blood-inclusive lungs was different between the two subgroups. Although all regressions were highly correlated, the fits of the blood-free ratio on ratios for blood-inclusive lung and blood together were better than for blood-inclusive lung alone. The mean error of prediction of extravascular lung water for all sheep was significantly less for the regression of blood-free ratio on ratios for blood and blood-inclusive lung together (11 g) than for blood-inclusive lung alone (18 g). This study shows that weights of lung homogenate and blood samples before and after simple oven drying can be used to provide accurate inexpensive estimates of postmortem extravascular lung water.

Animals↗
PubMed1985

Effects of alveolar hypoxia during partial mitral valve obstruction in unanesthetized sheep.

The effects of elevated left atrial pressure (Pla) on the pulmonary hemodynamic responses to hypoxia and infused prostaglandin-H2 analog (PGH2-A) were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied with isocapnic hypoxia (fraction of inspired O2, 0.12) or infused PGH2-A (0.2 to 1.0 micrograms X kg-1 X min-1 adjusted to increase pulmonary artery pressure (Ppa) by approximately 15 cm H2O) when Pla was normal or elevated to 10 or 20 cm H2O. The Pla was elevated by inflating a Foley catheter positioned in the mitral valve orifice. Elevation of Pla did not block the increase in Ppa or cardiac output (CO) caused by hypoxia but did block the increase in pulmonary vascular resistance (PVR). When Pla was elevated to 10 or 20 cm H2O, hypoxia caused Pla to increase further, and PGH2-A caused Ppa and PVR to increase whether Pla was elevated or not; PGH2-A did not cause CO to increase or Pla to increase further under any experimental condition. Neither hypoxia nor PGH2-A had any effect on left ventricular end-diastolic pressure under any experimental condition. We hypothesize that when Pla is elevated, the increase in CO may dilate the pulmonary circulation, obscuring hypoxic vasoconstriction. When Pla is elevated, the direct effects of hypoxic pulmonary vasoconstriction cannot overcome the increased intraluminal pressure, and PVR does not increase. The pulmonary vessels are still able to respond to a potent vasoconstrictor such as PGH2-A when Pla is elevated. We conclude that the further increase in Pla caused by hypoxia when Pla is elevated is primarily due to increased flow across a mitral valve behaving as a relatively fixed resistor.

Animals↗
PubMed1985

Lung mechanics in pulmonary edema.

Pulmonary edema can cause alterations in lung mechanics that directly contribute to clinical morbidity and mortality rates. Both the location of the edema fluid (interstitital versus alveolar pulmonary edema) and the etiology of the pulmonary edema contribute to the severity and type of abnormalities of lung mechanics observed. The alterations in lung mechanics associated with the adult respiratory distress syndrome may involve the direct effects of released mediators, alterations in pulmonary surfactant, and altered airway reactivity, as well as the direct effects of the edema fluid.

Animals↗
PubMed1984

Effects of granulocyte depletion on pulmonary responsiveness to aerosol histamine.

The effects of granulocyte depletion with hydroxyurea on pulmonary responsiveness to aerosol histamine were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied when granulocyte counts were normal (B), after 3 days of hydroxyurea but before granulocyte counts had dropped below 700 cells/mm3 (H), and after granulocyte counts had fallen below 200 cells/mm3 (D). Hydroxyurea itself had no effect on aerosol histamine responsiveness and the results were unaffected by the order of experimentation. All 10 sheep were less responsive (P less than 0.05) to aerosol histamine when granulocyte depleted effective dose of histamine that caused a reduction to 65% of control dynamic compliance (ED65Cdyn = 23.98 +/- 4.70 mg/ml) compared with base line (ED65Cdyn = 7.06 +/- 1.86 mg/ml). Those sheep initially most responsive to aerosol histamine had the greatest attenuation in their airway responsiveness to aerosol histamine (P less than 0.05). There was a significant negative correlation between absolute granulocyte counts in peripheral blood and pulmonary responsiveness to aerosol histamine during base-line (B) condition (r = -0.74, P less than 0.05) and for the data as a whole [r = -0.69, P less than 0.05 (B + H + D)]. Circulating granulocytes and/or pulmonary inflammation may contribute to pulmonary responsiveness to bronchial challenge.

Aerosols↗
PubMed1984

Effects of left atrial pressure elevation and histamine infusion on lung lymph in awake sheep.

To study the mechanism by which infused histamine increases lung fluid and solute exchange, the effects of left atrial pressure elevation (using a Foley catheter positioned at the mitral valve orifice) on lung lymph flow and protein content were studied in the presence and absence of histamine infusion in nine chronically instrumented unanesthetized sheep. In six sheep, histamine infusion (1-3 micrograms X kg-1 X min-1) was begun 2 h before increasing left atrial pressure by 10 and 20 cmH2O for 3 h each. Control experiments were performed on the same sheep to study the effects of left atrial pressure elevation alone and histamine infusion alone. Left atrial pressure elevation in the presence of histamine infusion did not cause a disproportionate increase in lung lymph flow nor was the lymph-to-plasma protein concentration ratio (L/P) different from left atrial pressure elevation alone. This argues against the presence of increased microvascular permeability at the time of these elevations. In three sheep, left atrial pressure was elevated by 20 cmH2O, and then histamine was infused at 2 micrograms X kg-1 X min-1. Histamine infusion caused a transient increase in L/P and a large increase in lymph flow, findings like those we have previously taken to represent an increase in microvascular permeability. However, L/P decreased to values comparable to those seen with elevated left atrial pressure alone. These observations suggest that histamine infusion may have a biphasic effect on lung lymph. There is an early (1-3 h) transient increase in lymph protein clearance that could result from a transient increase in permeability followed by a sustained increase in microvascular surface area. The early response is difficult to interpret because the changes are transient and could be affected by alterations outside the lung.

Animals↗
PubMed1984

Effect of aerosol histamine on lung lymph in awake sheep.

This study examined the effect of aerosol histamine on lung lymph in the awake sheep. Eleven sheep were chronically instrumented for measurement of lung lymph, lung mechanics, and vascular pressures. Aerosol histamine was given by use of a Collison nebulizer and delivered via a tracheostomy tube. Five breaths of a 30 mg/ml histamine solution caused lung lymph flow (QL) to increase from a base line of 5.5 +/- 0.5 (SE) ml/h to 14.3 +/- 1.5 (P less than 0.05) and the lymph-to-plasma protein concentration ratio (L/P) to increase from 0.63 +/- 0.02 to 0.72 +/- 0.02 (P less than 0.05). The concentration of aerosol histamine required to change QL by 30% (ED130QL) was determined by giving increasing concentrations of aerosol histamine every 15 min. The mean ED130QL was 22.2 mg/ml. The dose of histamine required to increase QL by 30% did not correlate (r = 0.04, n = 7) with the dose required to decrease dynamic compliance by 35%. The increase in QL lasted 100 +/- 19 min. Hourly exposure to five breaths of 30 mg/ml for 5 h caused a sustained increase in QL in two sheep and a waning effect in two sheep. The combination of aerosol histamine and elevated microvascular pressure (achieved by inflating a Foley catheter situated in the left atrium) caused changes in QL and L/P not totally consistent with the hypothesis that histamine increased pulmonary vascular permeability. Increased vascular permeability in the bronchial circulation was considered a likely explanation of the data.

Aerosols↗
PubMed1984

Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function.

Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out.

Acetylcysteine↗
PubMed1984

Effects of platelet depletion on the unanesthetized sheep's pulmonary response to endotoxemia.

The effect of platelet depletion on the unanesthetized sheep's pulmonary response to endotoxemia was studied in eight unanesthetized sheep. Platelets were depleted with rabbit anti-sheep platelet antibodies (APA). Bolus injections of APA alone caused marked pulmonary hypertension (PPA increased from 21 +/- 2 to 62 +/- 5 cm H2O +/- SE) and alterations in lung mechanics (dynamic compliance of the lung [Cdyn] decreased to 38.5 +/- 4.6% and resistance to air flow across the lung [RL] increased to 705 +/- 162% +/- SE of control), which were attenuated by pretreatment with meclofenamate. It was possible to deplete platelets before endotoxemia through a slow continuous infusion of APA without altering base-line values of the measured variables. Platelet depletion did not significantly attenuate the alterations in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, or the normal increase in lung lymph concentrations of thromboxane B2 or 6-keto-PGF1 alpha observed following endotoxemia in the sheep. We conclude that normal circulating platelet counts are not required for the full expression of the sheep's response to endotoxemia.

Animals↗
PubMed1983

Effect of endotoxin on airway responsiveness to aerosol histamine in sheep.

This study tested the hypothesis that in the awake sheep, airway responsiveness to aerosol histamine would be increased acutely by endotoxemia. Eleven sheep were chronically instrumented to allow for measurements of lung lymph flow, vascular pressures, and lung mechanics. Awake sheep were studied in a whole-body plethysmograph designed to measure dynamic compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC). Pulmonary responsiveness to aerosol histamine was assessed by giving five breaths of increasing concentrations of histamine (0.1-50 mg/ml) until Cdyn decreased to 65% (of control) or until 50 mg/ml of histamine had been given. Escherichia coli endotoxin (0.2-0.5 microgram/kg) was then infused, and at 5 h after endotoxemia pulmonary responsiveness to aerosol histamine was remeasured. After endotoxin, 9 of the 11 sheep exhibited decreased Cdyn at a lower concentration of histamine compared with the preendotoxin level (P less than 0.05). The mean of the log dose of histamine necessary to reduce Cdyn to 65% of control was 1.00 +/- 0.16 (SE) before endotoxin and 0.027 +/- 0.29 5 h after endotoxin; i.e., histamine responsiveness was increased. In the last 3 sheep studied, atropine (0.1 mg/kg iv) was given after the second aerosol histamine challenge, and a third dose-response curve was performed. Atropine did not return the endotoxin-induced increase in histamine responsiveness to base line. There was no correlation between the change in histamine responsiveness and the endotoxin-induced changes in Cdyn, FRC, RL, alveolar-arterial O2 difference, pulmonary arterial pressure, or lung lymph flow.

Aerosols↗
PubMed1983

Effect of granulocyte depletion on altered lung mechanics after endotoxemia in sheep.

To examine the role of circulating granulocytes in the airway changes caused by endotoxemia, we measured the response of chronically instrumented unanesthetized sheep to endotoxemia before and after granulocyte depletion with hydroxyurea. Granulocyte depletion did not affect the increases in mean pulmonary arterial pressure caused by endotoxin [peak pressure 59 +/- 8 cmH2O +/- (SE) control, 51 +/- 8 cmH2O granulocyte depleted]. However, the early (30-60 min after endotoxin) airway response to endotoxemia was markedly attenuated. Without granulocyte depletion, endotoxin caused dynamic compliance (Cdyn) to decrease to 41 +/- 10% of the base-line value and total lung resistance (RL) to increase to 283 +/- 61% of base line. When animals were granulocyte depleted, endotoxin decreased Cdyn to 69 +/- 6% (P less than 0.05) of base line and increased RL to 141 +/- 20% of base line (P less than 0.05). Granulocyte depletion also attenuated the effect of endotoxin on arterial oxygenation. During the maximum airway response to endotoxin, the alveolar-to-arterial oxygen gradient was 47 +/- 5 Torr in control studies and 32 +/- 2 Torr in granulocyte depleted studies (P less than 0.05). We conclude that interaction of granulocytes with the lung contributes to the changes in lung mechanics observed following endotoxemia and that the early pulmonary hypertension and the early alterations in lung mechanics caused by endotoxemia are caused by separate processes.

Agranulocytosis↗
PubMed1983

Correlation of oxygenation with vascular permeability-surface area but not with lung water in humans with acute respiratory failure and pulmonary edema.

We used a single-pass multiple tracer technique to measure cardiac output, extravascular lung water (EVLW) and lung vascular [14C]urea permeability-surface area (PSu) in 14 patients with acute respiratory failure and pulmonary edema. All patients had increased EVLW, but EVLW in the 10 surviving patients (0.26 +/- 0.06 SE ml/ml total lung capacity [TLC]) was not significantly different from that in the five patients who died (0.22 +/- 0.05). EVLW did not correlate with intravascular pressures or with alveolar-arterial oxygen pressure difference (A-aDO2). PSu was lower in surviving patients (0.50 +/- 0.16 SE ml/s X liter TLC) than in patients who died (3.44 +/- 0.36; P less than 0.05) and also lower than in previously reported data in patients with normal PSu. PSu correlated significantly with A-aDO2. Serial studies showed that PSu returned from a low value toward normal in a patient who survived but remained high in a patient who died. We conclude that the amount of edema in the lungs measured by indicator methods was not the principal determinant of either the magnitude of oxygenation defect or survival in the patients studied. We interpret the low PSu in surviving patients as decreased surface area and infer that the ability of the lung circulation to reduce perfusion of damaged and edematous areas was important in preserving oxygenation. A high PSu, presumably reflecting perfusion of areas with increased permeability, was a sign of especially poor prognosis. Multiple tracer techniques for measuring lung vascular PSu may help to define the pathogenesis and to evaluate therapies of acute lung injury in humans. Such measurements may be a more useful clinical tool than measurements of lung water in patients with acute respiratory failure and pulmonary edema.

Adult↗
PubMed1983

Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.

The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Effects of endotoxemia on cyclic nucleotides in the unanesthetized sheep.

The effects of endotoxemia on hemodynamics, pulmonary fluid, and solute exchange and cGMP and cAMP concentrations in lung lymph and pulmonary artery and left atrial blood were studied in six unanesthetized sheep. Cyclic AMP levels increased early in the endotoxin reaction, reaching peak concentration 1 hr after endotoxemia (during the period of pulmonary hypertension). Cyclic GMP levels increased gradually during the endotoxin reaction, reaching peak concentrations 5 hr after endotoxemia (during the period of "increased pulmonary vascular permeability"). The changes observed in cyclic nucleotide levels in lung lymph and pulmonary artery and left atrial blood suggested pulmonary production of cGMP but not cAMP. Cyclic AMP concentrations correlated with PPA, Qlymph, and a drop in the L/P ratio, whereas lung lymph cGMP correlated with an increased clearance of protein in the lymph. These results further characterize the sheep endotoxin reaction and suggest a possible role for cyclic nucleotides in the pathogenesis of the changes in lung vascular function that follow endotoxin infusion in sheep.

Animals↗
PubMed1982

Effect of changing lung mass on lung water and permeability-surface area in sheep.

The effects of changing cardiac output and lung mass on pulmonary capillary surface area, lung water, and hemodynamics were studied in eight sheep. 51Cr-erythrocytes, 125I-albumin, 3H2O, and [14C]urea were injected into the right atrium, and timed samples were collected from the aorta for the calculation of cardiac output (CO), extravascular lung water (EVLW), and permeability-surface area product (PS) for [14C]urea. CO was varied by opening and closing arteriovenous shunts, and lung mass was decreased by first tying off the left lung followed by tying off the right lower lobe. Pulmonary arterial pressure (r = -0.741) and pulmonary vascular resistance (r = -0.700) increased as lung mass was decreased. CO decreased slightly (r = -0.470 while left atrial pressure was not changed (r = -0.144) by decreasing lung mass. There was a close correlation between EVLW and lung mass (r = 0.944) and between [14C]urea PS and lung mass (r = 0.672). We were able to demonstrate that [14C]urea behaves as a diffusion-limited tracer in a single pass through the lungs, since [14C]urea extraction decreased as flow per unit mass increased. These results support the clinical use of multiple-tracer studies to measure EVLW and [14C]urea PS.

Animals↗
PubMed1982

Effect of histamine on lung mechanics in sheep. Comparison of aerosol and parenteral administration.

The purpose of this study was to examine the effects of parenteral and aerosol histamine on lung mechanics in sheep. Eleven sheep were chronically prepared with pulmonary arterial (PA) and left atrial (LA) catheters, a tracheostomy, and a silastic envelope in the pleural space. Unanesthetized sheep were studied in a pressure-compensated integrated-flow whole-body plethysmograph, and measurements of dynamic lung compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC) were made. Histamine was infused through PA or LA catheters or given as an aerosol at increasing concentrations until Cdyn decreased by 35%, RL doubled, or FRC increased by 25%. Parenteral histamine caused a reproducible decrease in Cdyn, a variable increase in RL, and no change in FRC. There were no significant differences between the LA and PA infusions. Aerosol histamine had similar effects to parenteral histamine, except some sheep did show an increase in FRC. Repeat studies in 3 animals showed PA histamine infusions to be highly reproducible, whereas changes associated with aerosol histamine were slightly less reproducible. Among sheep there was a several hundredfold range in responsiveness to either aerosol or parenteral histamine. There was a significant correlation (r = 0.98, p less than 0.001) between the parenteral histamine dose required for a response and the aerosol dose. These data were interpreted as suggesting that airway responsiveness to histamine is an inherent physiologic property.

Aerosols↗